Kinetics of circulating cell-free DNA for biomedical applications: critical appraisal of the literature

Abstract

Circulating cell-free DNA is considered as one of the major breakthroughs in the field of innovative diagnosis, used as a liquid biopsy. The kinetic parameters of a biomarker are mandatory to assess its usefulness as a diagnostic tool. Obtaining precise mathematical values for the kinetic parameters (e.g., half-life) is then crucial because it could be used for therapeutic monitoring as a prognostic factor. However, little is known about the intrinsic properties of circulating cell-free DNA, more especially, its kinetic properties within the organism. We summarized the basic principles that may affect the kinetics of circulating cell-free DNA within the organism in the light of biological and clinical evidence. We also meta-analyzed the reported data in the literature and the methodologies that have been used to study the kinetic parameters of human circulating cell-free DNA in vivo.

Keywords: biomarkers; cell-free DNA; half-life; personalized medicine; pharmacokinetics.

Figure 1.. Physiological barriers seem to affect the distribution of tumor-derived cell-free DNA.

BBB: Blood–brain barrier; ctDNA: Circulating tumor DNA. Reproduced with permission from [4] © The American Association for the Advancement of Science (2018).

Figure 2.. Illustration of cfDNA distribution within the organism based upon identified processes and raised questions.

cfDNA: Cell-free DNA; csb-cfDNA: Cell-surface-bound cfDNA.

Figure 3.. Flow chart of the included studies in the meta-analysis.

Figure 4.. Concentration versus time curve with a shape characteristic of two rate of concentration decrease (two-compartment model).

(a) Decreased concentration from the blood due to distribution and elimination process; (b) Inflexion point or pseudo-equilibrium state; (c) Decreased concentration from the blood due to elimination only (log-linear terminal phase); slope permits to calculate half-life of elimination (t_λz).

Figure 5.. Importance of the window blood sampling.

(A) Window blood sampling with t_f = 3 h and (B) window blood sampling with t_f = 10 h for the same entity. In the first case (A), the window is too short and the elimination phase is not described alone. The slope (1.59 h-1) could be considered as the rate of elimination whereas it is the consequence of distribution and elimination process. If an optimal design is obtained (including later points ‘×’, case [B]), the real elimination rate is close to 0.1 h-1. t_f: Time of the last sample obtained during assay.